Activation and repression of immune responses is controlled by signals from activating and inhibitory Fc receptors expressed on immune system cells. Impairment of the functional balance between activating and inhibitory receptors leads either to hyperactivity to foreign and self antigens or to unresponsiveness, as seen in many autoimmune diseases and infections. The Fc receptor like molecules 1-6 (FCRLs) are encoded by a family of genes recently identified on the basis of sequence similarity with previously identified Fc receptors. FCRL2 is a member of this family whose expression is limited to B cells. The FCRL2 transmembrane protein has four C2 type extracellular Ig-like domains and an uncharged transmembrane segment. The cytoplasmic tail contains one potential activation motif (ITAM) and two consensus inhibitory motifs (ITIM), which can be phosphorylated by kinases. Tyrosine phosphorylation triggers a downstream signaling cascade leading to cell activation, while the phosphorylated ITIMs serve as docking sites for phosphatases, which inhibit cell activation. The signaling potential and function of FCRL2 has not yet been determined. This proposal focuses on how human FCRL2 signaling regulates B cell function. Aim I focuses on identifying which B cells express FCRL2. FCRL2 expression may fluctuate during peripheral B cell differentiation;therefore, if the expression of FCRL2 is limited to specific B cell subsets, it may be useful as a diagnostic marker. Aim II focuses on assessing the signaling capacity of FCRL2 and the signaling pathways that respond to FCRL2 activation using chimeric receptors containing mutations of tyrosine residues. Aim III focuses on the phenotypic effects of FCRL2 signaling on B cell viability;whether signaling through FCLR2 leads to cell proliferation or death. If FCRL2 functions as an activating receptor, it may be important in B cell signaling in response to foreign antigens. If FCRL2 instead functions as an inhibitory receptor, it may play a role in dampening B cell activation during infection. Its deregulation could also play a role in autoimmunity or immune suppression. An understanding of which B cells express FCRL2 and how FCRL2 functions is critical to understanding its role in regulating immune responses.